For compositions having sustained-release properties, there are, for example, solid sustained-release medicines. The solid sustained-release medicines are very useful for controlling the blood level of the active ingredient(s), reducing the frequency at which the medicine must be taken; prolonging the effect of active ingredients that have a short half-life; and reducing the side effects of the active ingredients that have a narrow range between a minimum effective blood concentration and a side effect exhibition concentration. Regarding conventional solid sustained-release medicine, there are matrix type sustained-release tablets that use a hydrophilic polymer capable of forming a gel upon contact with water, and reservoir type sustained-release capsules that enclose granules of medicine. The granules within the capsules are formed by coating core particles with an active ingredient(s) and then coating the surface of the coated particles with a coating film capable of imparting sustained-release properties. Tablets are preferable to capsules and granules from the viewpoint of ease of taking, but reservoir sustained-release tablets have been disadvantageous in that when the sustained-release granules are compressed into the tablets, the coating film capable of imparting sustained-release properties is destroyed, so that the controlled release of the active ingredient(s) by dissolving becomes difficult.
On the other hand, patent document 1 and the like describe that hydrophilic polymers such as methyl cellulose (MC), hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC) can be used as a release-sustaining base ingredient used in the matrix type sustained-release preparations. These hydrophilic polymers are advantageous, for example, in that they impart sustained-release properties by the formation of a complete gel layer by hydration in a solution having a low ionic strength, are hardly affected by pH, and are excellent in the stability of release by dissolution over a long period of time. They, however, have a problem, which is called dose dumping. If dose dumping occurs, it becomes impossible to hydrate the polymer in a solution having an intermediate or higher ionic strength, their gelation is suppressed, so that a large portion of the active ingredient(s) of a pharmaceutical preparation designed to have sustained-release properties is rapidly released, thus, the preparation exhibits no sustained-release properties. When the dose dumping occurs, the resulting rapid increase of the active ingredient(s) in the blood can induce death, depending on the efficacy of the active ingredient(s) that have a narrow range between the minimum blood level and the concentration where side effects are exhibited. Since the value of ionic strength in the gastrointestinal tract varies depending on regions of the tract and the food consumed, there has been a desire for a release-sustaining base ingredient which makes it possible to avoid the dose dumping in a wide ionic strength value range throughout the gastrointestinal tract.
Patent documents 2 to 5 describe simultaneous use of pregelatinized starch and a hydrophilic polymer such as hydroxypropyl cellulose or hydroxypropylmethyl cellulose as a means for avoiding the dose dumping. However, the pregelatinized starch (preferably drum-dried waxy corn starch) used in patent document 2 has no sustained-release effect in itself and is such that sustained-release properties are imparted by an ingredient other than the pregelatinized starch. In addition, the pregelatinized starch is disadvantageous in that the pregelatinized starch has only auxiliary effect on the release-sustaining base ingredient, because both the base ingredient and this auxiliary are necessary and the amounts added should be large, resulting in an increased size of a preparation. Patent documents 3 to 5 describe that the tablet tensile strength of pregelatinized starch at a solid fraction of 0.8 is 0.15 kN/cm2. They, however, do not describe the upper limit of the tablet tensile strength. The tensile strength of the pregelatinized starch used in the comparative examples in these patent documents is 0.220 to 0.323 kN/cm2, while the tensile strength of the functional starch powder of the invention is 0.7 to 1.5 kN/cm2. Thus, they are clearly different. In patent documents 2 to 4, sustained-release properties are imparted by a combination of pregelatinized starch and hydroxypropylmethyl cellulose. These documents, however, neither describe nor suggest that starch having a tensile strength of 0.15 kN/cm2 or more imparts sustained-release properties by itself. In addition, no starch having a tensile strength of more than 0.323 kN/cm2 has been reported.
As starch used in the fields of medicines, agrochemicals, fertilizers, feed, food, industry, cosmetics, etc., there are pregelatinized starch, partly pregelatinized starch, crosslinked starch and the like. They are used as a disintegrating agent mainly in the medicine field.
All of the starches described in patent documents 6 to 15 rapidly collapse and do not impart any sustained-release properties. They are essentially different in the following respects from the starch of the invention, from which tablets that contain 60 to 100% of the starch powder are not disintegrated in 3 hours or more. That is, the modified starch of patent document 6 has a low degree of swelling of 2.5 to 12 and breadks down in 30 minutes. The tablets of patent document 7 that contain waxy starch disintegrate such that tablets containing 50% of the waxy starch are disintegrated within 60 seconds. The tablets of patent document 8 contain β-starch with an α-starch surface and tablets containing 17 to 30% of the β-starch are disintegrated within 2 minutes. The tablests of patent document 9 containing β-starch having 1 to 4% of α-starch adhered thereto disintegrate such that tablets containing 17 to 87% of this β-starch are disintegrated within 20 seconds. The starch of patent document 10, which is obtained by 5 to 20% pregelatinization of the surface of β-starch, breaks down within 2 minutes. The modified starch of patent document 11 has a cold-water-soluble matter content of 10 to 20%, and tablets containing 64 to 80% of this modified starch are disintegrated within 20 minutes. The processed starch of patent document 12 has a low degree of swelling of 3.0 to 6.0 and the tablets containing 10% of this processed starch are disintegrated within 6 minutes. The processed starch of patent document 13 has a cold-water soluble matter content of less than 10% by weight, a small swelling volume of 3 to 15 ml/g and a low water retention capacity of at most 610% and breaks down within 2 minutes. The starch of patent document 14 is a cross-linked starch powder having a low swelling property (swelling property in cold water: 3 to 25 ml) and breaks down more rapidly than Starch 1500 (Comparative Example 6). The processed starch of patent document 15 has a small swelling volume of 3 to 15 ml and is the starch represented by PCS (Comparative Example 5) and Starch 1500 (Comparative Example 6). Thus, these starches are essentially different from the starch of the invention.
Patent documents 16 to 20 describe a starch is used as a matrix base ingredient. Patent document 16 describes that matrix tablets are made of a high-molecular weight polysaccharide existing in nature. This document, however, describes only working examples relating to xanthan gum and no working example using starch and does not specifically describe starch capable of imparting sustained-release properties. Patent document 17 describes that a matrix agent substantially contains a crystalline straight-chain glucan and a glucan-degrading reagent. The straight-chain glucan, however, refers to amylose. The functional starch powder of the invention is different from the matrix agent because it contains amylopectin besides amylose as described hereinafter. In addition, in the case of the functional starch powder of the invention, the glucan-degrading reagent is not necessary for controlling the release of an active ingredient. Patent document 18 describes that a matrix raw material substantially contains a crystalline straight-chain glucan. This document, however, describes that amylopectin is removed from starch. The functional starch powder of the invention is different from the matrix raw material because it contains amylose and amylopectin.
Patent document 19 describes that the core tablets of film-coated tablets contain pregelatinized starch having an average degree of pregelatinization of 35 to 95%. Since the average degree of pregelatinization of the functional starch powder of the invention ranges from 40 to 98%, it is difficult to distinguish the starch of the invention from that of patent document 19 only by the average degree of pregelatinization. The functional starch powder of the invention, however, is clearly different from the latter, for example, in gel indentation load and the amount of swollen or dissolved amylose and amylopectin. The purpose of the starch of patent document 19 is to prevent the tablets from being impregnated with a liquid at the time of coating, and hence is obviously different from that of the functional starch powder of the invention. The coated tablets (the amount of the starch used: 14 wt %) themselves have excellent disintegrating properties. From these facts, it is clear that the starch of patent document 19 does not control the release of a drug. Patent document 20 describes spherical fine particles wholly or partly composed of a water-insoluble cottony polysaccharide. The fine particles of patent document 20 are produced, for example, by a biocatalyst process using starch synthase. On the other hand, the functional starch powder of the invention is produced only by heat treatment without using a catalyst such as an enzyme. Thus, the functional starch powder is obviously different from the fine particles of patent document 20. As to the shape of the functional starch powder of the invention, the functional starch powder comprises starch particles with a particle size of 50 to 100 μm having a structure formed by indenting a sphere or an oval in one or more parts thereof. Thus, the functional starch powder is clearly different from the fine particles of patent document 20, i.e., the spherical fine particles of 1 nm to 100 μm having a narrow particle size distribution. Patent document 21 describes starch particles obtained by drying an emulsion of an active ingredient and starch which has an amylopectin content of 65% or more and 80% by weight or more of which has a limited molecular weight of 10 to 10000 kDa. This starch, however, is water-soluble and the functional starch powder of the invention is different from the starch because it contains a water-insoluble component. Patent document 22 describes a method for making starch and a material into a slurry in a saturated aqueous salt solution and making the slurry into capsules, which includes blowing steam through starch at a pressure of at least 110 psi (0.78 MPa) in the presence of a salt to disperse the starch completely, heating the resulting starch slurry to a temperature of 120 to 180° C. at 55 to 120 psi (0.39 to 0.84 MPa) or more, and immediately exposing the slurry to atmospheric pressure to lower the temperature to 112° C. or lower. However, when the salt is present, amylose is precipitated, so that the product obtained by the method is not the starch particles according to the invention, i.e., starch particles with a particle size of 50 to 100 μm having an indentation in one or more parts thereof but a filmy and leaf-like product formed by the crystallization of amylose. Therefore, the product is different in shape from the fine particles according to the invention.
On the other hand, pregelatinized starch is used mainly in the food field as a thickening agent, feed for eel breeding or the like has been disadvantageous in that a gel formed by the starch is destroyed in the presence of α-amylase, resulting in a deteriorated release-sustaining capability, as reported in Chem. Pharm. Bull., 35(10)4346-4350(1987). It has been disadvantageous also in that at a high ionic strength, and it loses release-sustaining properties.
Patent document 1: U.S. Pat. No. 6,296,873
Patent document 2: JP-T-2002-541090
Patent document 3: WO200410997
Patent document 4: WO200410998
Patent document 5: WO200411002
Patent document 6: JP-B-46-21471
Patent document 7: JP-A-48-68726
Patent document 8: JP-B-53-3275
Patent document 9: JP-B-62-7201
Patent document 10: JP-B-58-27774
Patent document 11: JP-B-56-11689
Patent document 12: JP-A-58-32828
Patent document 13: JP-B-59-47600
Patent document 14: JP-B-63-7531
Patent document 15: JP-A-6-100602
Patent document 16: JP-T-10-512873
Patent document 17: JP-T-7-508532
Patent document 18: JP-T-7-508533
Patent document 19: JP-A-2002-193792
Patent document 20: JP-T-2001-514315
Patent document 21: US20030180371
Patent document 22: U.S. Pat. No. 4,755,397